Biological Reactive Intermediates III: Mechanisms of Action by Van Rensselaer Potter (auth.), James J. Kocsis, David J.

By Van Rensselaer Potter (auth.), James J. Kocsis, David J. Jollow, Charlotte M. Witmer, Judd O. Nelson, Robert Snyder (eds.)

This quantity comprises the lawsuits of the 3rd in a chain of meetings entitled, The foreign Symposium on organic Reactive Intermediates. the 1st used to be held on the collage of Turku in Finland, in 1975, the second one on the college of Surrey within the uk, in 1980 and the newest on the college of Maryland within the usa, in 1985. the importance of those meetings has been emphasised by means of the quick progress of mechanistic toxicology during the last decade. those meetings have been at first inspired by way of the try to discover the importance in the back of the observations that the toxicity of carcinogenic responses produced through many chemical compounds used to be linked to the commentary that their metabolism resulted in the formation of chemcially reactive electrophiles which covalently guaranteed to nucleophilic websites in cells comparable to proteins, nucleic acid or fat. lately, more moderen innovations have arisen that have necessitated the growth of matters coated via the convention. for instance, the applying of more recent wisdom of the position of energetic oxygen species in reactive metabolite formation, the concept that of suicide substrates, exam of the functionality of glutathione in cells, software of immunological suggestions and molecular organic probes to the answer of toxicological difficulties all had an influence at the examine of the organic reactive intermediates.

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Extra info for Biological Reactive Intermediates III: Mechanisms of Action in Animal Models and Human Disease

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4-diol-l,2-epoxide-l. 2-epoxide. at 25 °c in 1:9 dioxane:water. 1 (NaCI04)' The flat portion of the curves corresponds to ko whereas the portion with a slope of -1 corresponds to k H• keto diol 29 presumably derived from hydride migration to the benzylic position; this latter product is generally observed from isomer-l but not from isomer-2. except in the presence of unusual conformational factors. 27 In 1976. we proposed 2 that the chemical reactivity. and hence possibly one aspect of the biological activity.

According to these views the tritium lost fran bound residues should be found as tritiated water. When incubations were alkalinized, extracted with ether, and lyophilized, the recovered water contained negligible C-14 but substantial tritium; in fact the amount of tritiated water was several times the amount that could be accounted for by the tritium deficit in the covalently bound material. The TIC ratios in lung and kidney are significantly higher than those for liver, but these too indicate a significant role for secondary, 35 more highly oxidized metabolites in covalent binding.

Jerina, Stereoelectronic factors in the solvolysis of bay region diol epoxides of polycyclic aromatic hydrocarbons, J. Am. Chem. Soc. 100:5218 (1978). R. Thakker, H. Vagi, W. Levin, A. W. Wood, A. H. Conney, and D. M. Jerina, Polycyclic aromatic hydrocarbons: Metabolic activation to ultimate carcinogens, in: "Bioactivation of Foreign Compounds," M. W. , Academic Press, New York (1985) p. 177. Levin, P. E. Thomas, L. M. Reik, A. W. Wood, and D. E. Ryan, Multiplicity and functional diversity of rat hepatic microsomal cytochrome P450 isozymes, in: "IUPHAR 9th International Congress of Pharmacology," Vol.

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